Biological

Psychiatry:

Archival Report Celebrating

50 Years

Strengthened Hippocampal Circuits Underlie

Enhanced Retrieval of Extinguished Fear
Memories Following Mindfulness Training
Gunes Sevinc, Britta K. Hölzel, Jonathan Greenberg, Tim Gard, Vincent Brunsch,
Javeria A. Hashmi, Mark Vangel, Scott P. Orr, Mohammed R. Milad, and Sara W. Lazar

ABSTRACT
BACKGROUND: The role of hippocampus in context-dependent recall of extinction is well recognized. However, little
is known about how intervention-induced changes in hippocampal networks relate to improvements in extinction
learning. In this study, we hypothesized that mindfulness training creates an optimal exposure condition by
heightening attention and awareness of present moment sensory experience, leading to enhanced extinction
learning, improved emotion regulation, and reduced anxiety symptoms.
METHODS: We tested this hypothesis in a randomized controlled longitudinal study design using a 2-day fear
conditioning and extinction protocol. The mindfulness training group included 42 participants (28 women) and the
control group included 25 participants (15 women).
RESULTS: We show that mindfulness training is associated with differential engagement of the right supramarginal
gyrus as well as hippocampal-cortical reorganization. We also report enhanced hippocampal connectivity to the
primary sensory cortex during retrieval of extinguished stimuli following mindfulness training.
CONCLUSIONS: These findings suggest hippocampal-dependent changes in contextual retrieval as one plausible
neural mechanism through which mindfulness-based interventions enhance fear extinction and foster stress
resilience.
Keywords: Extinction, Extinction retrieval, Fear memory, fMRI, Hippocampus, Mindfulness
https://doi.org/10.1016/j.biopsych.2019.05.017

The ability to recall that a stimulus is no longer associated with
threat is crucial to healthy emotional functioning and is a major
component of emotion regulation (1–3). This ability serves as
the basis for exposure-based therapies and is critical to treat a
variety of disorders including phobia, trauma, and other anxiety
disorders (4,5). During exposure-based therapies, individuals
are presented with fear-inducing stimuli in a controlled envi-
ronment until the response to the eliciting stimulus gradually
declines while behavioral patterns of avoidance that reinforce
the fear response dissolve (6). Mindfulness meditation is
thought to create a state of optimal exposure (7,8) in which
aversive stimuli are experienced with nonreactive acceptance
(7,8), and facilitate extinction learning. Mindfulness-enhanced
extinction learning and the neural mechanisms associated
with this enhancement, however, have not been fully explored.
Extinction learning entails the formation of a new associa-
tion and consists of separate processes of acquisition,
consolidation, and retrieval (9–11). The hippocampus is critical
to the consolidation and retrieval processes and gates the
expression of either the conditioned fear or extinction memory,
depending on contextual information (12–15). Mindfulness
training leads to improvements in memory (16,17) as well as to
changes in hippocampal structure and function (18–20).
Relying on the critical role of the hippocampus in context-
dependent retrieval of extinguished stimuli and the concep-
tual similarity between therapeutic exposure and mindful
awareness, we hypothesize that mindfulness training might
lead to improvements in extinction learning through alterations
in hippocampal functioning during retrieval. Furthermore, core
components of mindfulness training include attention control,
emotion regulation, and sensory awareness (21). Investigations
into the effects of mindfulness interventions on a range of
health outcomes have also identified alterations in somato-
sensory processing (22,23) and attentional networks as med-
itators of these improvements (24,25). Given the role of
attention in retrieval, and the critical role of corticohippocampal
networks, we hypothesize that training-dependent changes in
these networks might also contribute to changes in extinction
learning and retrieval.
We tested these hypotheses in a randomized, controlled
study using a well-established fear conditioning and extinction
paradigm adapted for the magnetic resonance imaging (MRI)
environment before and after an 8-week mindfulness-based
stress reduction (MBSR) or exercise-based stress manage-
ment education (SME) program (1,13,26). This active control
condition was matched to MBSR in the amount of facilitator

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ª 2019 Society of Biological Psychiatry. This is an open access article under the 693
CC BY license (http://creativecommons.org/licenses/by/4.0/).
ISSN: 0006-3223 Biological Psychiatry November 1, 2019; 86:693–702 www.sobp.org/journal
Biological
Psychiatry:
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50 Years
contact and home practice assigned to allow for an exami-
nation of mechanisms of action specific to mindfulness
training. Importantly, because exercise is well known to pro-
mote emotion regulation (27), as well as enhance hippocampal
structure and function (27,28), we expected comparable in-
creases in functional engagement of the hippocampus for both
interventions. However, assuming different mechanisms of
action, we hypothesized that mindfulness training would
differentially impact the functional connectivity of hippocampal
networks, predominantly in regions associated with attention,
sensory awareness, and contextual processing.
METHODS AND MATERIALS
Participants
Subjects 18 to 50 years of age were recruited via public
transportation advertisements for stress-reduction programs.
In addition to the standard MRI safety exclusion criteria, par-
ticipants were required to be right-handed, have no current
psychiatric or neurological disorders, and not be engaged in
psychotherapy or have taken psychotropic medications within
12 months prior to the study. They were required to have had
minimal prior experience with meditation or yoga practice, as
defined by having taken no more than 4 meditation classes of
any kind in the past 12 months, or more than 10 classes in their
lifetime. Participants were remunerated up to $100 for
participation.
Participants were randomized to 1 of 2 stress reduction
programs, MBSR or SME on a 2:1 ratio, stratified by gender.
This ratio was chosen to maximize power for correlational
analyses in the MBSR group. In total, 94 participants
completed initial testing and were randomized; 89 attended at
least 1 class (58 MBSR, 31 SME), and 49 MBSR and 27 SME
participants completed MRI scanning at the post time point.
The Partners HealthCare Institutional Review Board approved
the study protocol; all participants provided written informed
consent. There were no differences between groups in terms
of gender (MBSR: 28 women, 14 men; SME: 15 women, 10
men [c21 = 0.30, p = .58]), age (MBSR 31.14 6 7.71 years; SME
33.08 6 18.02 years [t65 = 20.94, p = .35]), or years of edu-
cation (MBSR 17.40 6 3.08 years, SME 18.02 6 2.51 years
[t65 = 20.84, p = .40]). The minimum number of participants
who fully completed self-report measures was 37 for MBSR
and 22 for SME. The number of participants who had func-
tional neuroimaging data available at day 2 was 42 for MBSR
and 25 for SME. The total hours of home practice was 23.50 6
10.87 hours for MBSR and 34.82 6 19.74 hours for SME.
Questionnaires
Questionnaires included the Perceived Stress Scale (PSS) (29),
Spielberger State–Trait Anxiety Inventory (30), the Difficulties in
Emotion Regulation Scale (DERS) (31), and the Mindful
Attention Awareness Scale (32). Repeated-measures t tests
and analyses of covariance were used to determine statistically
significant differences within and between the groups on the
behavioral outcome measures using SPSS version 24 (IBM
Corp., Armonk, NY). From the MBSR group, 37 completed the
Perceived Stress Scale, State–Trait Anxiety Inventory, and
Mindful Attention Awareness Scale questionnaires, and 39
694 Biological Psychiatry November 1, 2019; 86:693–702 www.sobp.org/journal
Enhanced Retrieval of Extinguished Fear
completed the DERS questionnaire; from the SME group these
numbers were 22 and 23 participants, respectively.
Fear Conditioning and Extinction Paradigm
The scanning protocol comprised a 2-day classical fear con-
ditioning and extinction paradigm validated in healthy subject
(4,33) and patient (1,2,34) populations. Briefly, the fear-
conditioning procedure consisted of acquisition (“condition-
ing”) and extinction phases on day 1, and a delayed extinction
recall phase on day 2. Skin conductance responses were
collected and scored as previously described (2,13) (see the
Supplement). Owing to low data quality and low compliance
with our criteria (i.e., to exhibit signal changes during condi-
tioning), only16 participants had both functional neuroimaging
and skin conductance data (8 per group).
Image Acquisition
Imaging data were acquired on a Siemen’s Prisma 3.0T
equipped for echo-planar imaging (Siemens Medical Systems,
Iselin, NJ) with a 32-channel gradient head coil. An automated
scout image was obtained to facilitate alignment of pre- and
postintervention scans. High-resolution 3-dimensional
magnetization prepared rapid acquisition gradient-echo se-
quences were acquired (repetition time/echo time/flip angle =
2.53 ms/1.74 ms/7 degrees; 1-mm isotropic voxels; field of
view = 256 cm; 176 axial slices). Functional images were ac-
quired with gradient-echo T2*-weighted sequences (repetition
time/echo time/flip angle = 3 seconds/30 ms/90 degrees; field
of view = 1400 3 1400; slice thickness = 2.5 isotropic voxels).
Functional MRI Data Analysis
All participants (n = 76) were scanned within 2 weeks before
and after the courses. Data from 9 participants were unusable
owing to technical problems during scanning (n = 2) or clerical
errors (n = 7). Usable data were available for 42 MBSR and 25
SME participants. Functional data were analyzed using SPM12
(Wellcome Department of Neurology, London, United
Kingdom), using standard preprocessing pipeline (see the
Supplement). Both whole-brain and a priori region-of-interest
(ROI) analyses were conducted. Neural activations within the
hippocampi were examined using atlas-based anatomical
ROIs (Neuromorphometrics atlas in SPM12). Similar to Milad
et al. (13), additional correlation analyses were conducted to
examine the relationship between the fMRI blood oxygen
level–dependent (BOLD) signal changes in the hippocampus
during extinction recall and the magnitude of the psycho-
physiological index of extinction memory recall at baseline. For
the correlation between index of extinction memory and neural
signal estimates, we used peak coordinates previously re-
ported in Milad et al. (13) and extracted signal values from this
ROI using MarsBaR (35) using a sphere with a radius of 6 mm,
and using the extinguished stimuli (CS1E) in reference to
baseline fixation contrast. This ROI will be referred as func-
tional ROI, while atlas-based ROIs will be referred as
anatomical ROIs. To assess differences between groups in
terms of b estimates within the a priori functional ROI, an
analysis of variance was used. For the event-related analysis, a
trial averaging window of 21 seconds beginning 6 seconds
prior to the trial onset was used. The contrast of interest at the
 Biological
Psychiatry:
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Enhanced Retrieval of Extinguished Fear 50 Years

first level was CS1E versus conditioned stimulus never paired
with the shock (CS–) and allowed us to assess neural
responses that were specific for extinction recall. These first-
level analyses were subjected to a second-level analysis
using a fully flexible factorial design with the following factors:
subject, time (pre and post), and group (MBSR and SME).
Task-related responses were considered to be significant at a
threshold of p , .001 at the voxel level and at a threshold of p
, .05 using familywise error (FWE) correction at the cluster
level. b estimates from the peak were then extracted to inter-
pret the interaction effect.
For analysis of functional connectivity, we performed seed-
based connectivity analysis using the weighted general linear
modeling option in the CONN toolbox (36) (see the Supplement
for details). The seed was an anatomical ROI of the entire left
hippocampus, based on the parcellation scheme of the
Harvard-Oxford Atlas. The results reflect connectivity of the
ROI to the whole brain. For reconstruction and segmentation of
the brain, FreeSurfer image analysis suite version 5.3 was used
following the longitudinal analysis stream (37–39). For the an-
alyses of the relationship between structure and function,
symmetrized percent change in gray matter intensity was used
(38) (see the Supplement for details). Studies of patient pop-
ulations (2) and rodents (4) have demonstrated that a subset of
functional alterations in neural processes related to the gating
of the conditioned or extinguished memory were more robust
during the early phases of extinction recall. Furthermore, it has
been hypothesized that additional extinction learning may take
place during the retrieval phase, which can potentially
confound neural activity associated with extinction recall in
later phases (2). Thus, all analyses were performed twice, first
using all extinction recall trials, and then using only the first 4
CS1E extinction recall trials.
RESULTS
Mindfulness Training Leads to Improvements in
Anxiety and Emotion Regulation
As expected, both MBSR and SME decreased levels of
perceived stress (MBSR [n = 37]: DPSS = 4.57 6 8.04 [t36 =
3.45, p , .001, Cohen’s d = 0.56 (95% confidence interval,
1.89–7.25)]; SME [n = 22]: DPSS = 3.68 6 6.52 [t21 = 2.65, p =
.015, Cohen’s d = 0.57 (95% confidence interval, 0.79–6.57)]),
with no statistical difference between groups in DPSS scores
(t59 = 20.44, p = .66) (Figure 1C). Three 1-way analyses of
covariance were conducted to compare levels of mindfulness,
anxiety, and emotion regulation at post while controlling for
baseline levels. Levene’s test and normality checks were car-
ried out and the assumptions were met for the Mindful Atten-
tion Awareness Scale and State–Trait Anxiety Inventory. The

A Study design B Fear conditioning and extinction paradigm

Pre Intervenons Post

Condioning Recall

Mindfulness
fMRI fMRI
( 2-day ) ( 2-day )
Control
Exncon

Day 1 Day 2

C Self report measures

Perceived stress Emotion regulation Anxiety
25 120 60
100 50
20 80 40
60 30
15 40 20
20 10
10 0 0
MBSR SME MBSR SME MBSR SME

pre post pre post pre post

Figure 1. (A) Study design, (B) fear conditioning and extinction paradigm, and (C) changes in outcome measures. Error bars reflect standard deviations.
Both interventions decreased perceived levels of stress; however, mindfulness-based stress reduction (MBSR) was associated with further improvements in
anxiety and emotion regulation levels. fMRI, functional magnetic resonance imaging; SME, stress management education.

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Biological
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results suggested that there was a marginally significant
difference in anxiety scores between the 2 groups at post
(F1,59 = 3.93, p = .052, partial h2 = .63). For the DERS, a
Shapiro-Wilk test of standardized residuals suggested a non-
normal distribution at p = .37. A replication of 1-way analyses
of covariance with log-transformed DERS scores suggested
no statistically significant differences between the 2 groups
(F1,59 = 1.391, p = .243, partial h2 = .23). There were also no
differences between the MBSR and SME groups in terms of
mindfulness levels (F1,59 = 3.251, p = .77, partial h2 = .55).
Hippocampal Activity During Recall at Baseline
We examined BOLD signal in both hippocampi using an atlas-
based ROI during extinction recall for all subjects at baseline. A
significant cluster in the left hippocampus was identified
(cluster size [k = 19, 152 mm3]), peak Montreal Neurological
Institute (MNI) coordinates (218, 230, 28) (FWE p = .015)
(Figure 2A). A significant positive correlation was found be-
tween the extinction retention index (ERI) values and baseline
hippocampal activity using parameter estimates extracted
from this functional ROI with the peak voxel reported by Milad
et al. (13), which reflects the ability to remember that a stimulus
is no longer associated with threat (Pearson’s r = .79, p , .001,
n = 16) (Figure 2B). Stronger BOLD signals in the hippocampus
were associated with larger ERI values.
Hippocampal Structural and Functional Changes
During Recall Following the Interventions
There were no statistical differences between the 2 groups in
terms of changes in ERI (MBSR: DERI = 0.68 6 30.50; SME:
DERI = 26.81 6 51.2) (t14 = 1.24, p = .24). An independent-
samples t test using symmetrized percent change values
revealed no significant changes in the left hippocampal in-
tensity between the MBSR (0.157 6 1.09) and the SME (0.055
6 1.20) (t59 = 20.962, p = .34) groups. BOLD signal contrast
estimates from the left hippocampus were extracted using the
a priori functional ROI. A repeated-measures analysis of vari-
ance revealed a significant main effect of time (Figure 2C)
(F1,65 = 14.423, p , .001), but no group-by-time interaction
(F1,65 = 1.063, p = .306). An exploratory analysis for within-
group differences using a paired-samples t test demon-
strated a significant increase for the MBSR group (t41 = 4.765,
p = .000) and a nonsignificant increase for the SME group (t24 =
1.411, p = .171).
Mindfulness Training Enhances Activity in
Supramarginal Gyrus During Extinction Recall
A whole-brain group-by-time analysis of BOLD signal during
recall of extinguished stimuli using the CS1E versus CS–
contrast identified differential engagement of a cluster in the
right supramarginal gyrus (rSMG) (Figure 3A) (MNI coordinates
[56, 240, 24]; Brodmann area 40; FWE p = .026). Investigation
of the contrast estimates for each group at each time point
indicated a larger increase for the MBSR group (n = 42)
compared with the SME group (n = 25) from pre- to post-
intervention (Figure 3B). Postintervention b estimates from this
cluster significantly correlated with the total number of minutes
of reported mindfulness practice at home for the MBSR group
(r39 = .378, p = .018) (Figure 3C).
Mindfulness Training Increases Functional
Coupling of the Hippocampus to Sensory Cortex
During Extinction Recall
To test our hypothesis that MBSR and SME lead to differential
changes in hippocampal functional coupling, we performed a
group-by-time whole-brain analysis using an atlas-based left
hippocampus seed. This analysis did not yield any significant
results (FWE p . .05). However, a within-group analysis
demonstrated that MBSR (n = 42), but not SME (n = 25),
resulted in an enhanced functional coupling between the hip-
pocampus and right primary sensory cortex (Figure 3D) (MNI
coordinates [52, 228, 56]; k = 139; FWE p = .027). This region
of the sensory cortex is typically associated with the left hand
(40) and is consistent with placement of the shock electrodes
in the present study.
Secondary whole-brain analysis using the initial 4 trials of
extinction recall and an atlas-based left hippocampus seed
identified a significant increase in the functional connectivity

A ROI analyses CS+E [pre] B Associaon between hippocampal C ROI analyses CS+E [group x me]
acvaon and exncon retenon [pre]
hippocampus

120
0.8
Extinction retention index

pre post
100

80 0.6
beta estimates

60 0.4
40
0.2
20
0
0

-20 -4 -2 0 2 4 6 -0.2

-40
-0.4
MNI coordinates [-18 -30 -8 ] Parameter estimates at hippocampus MBSR SME

Figure 2. (A) Region-of-interest (ROI) analyses showing blood oxygen level–dependent (BOLD) signal in the hippocampus (left) during recall of extinguished
stimuli for all participants at baseline. (B) Regression plot showing a positive correlation between the extinction retention index and parameter estimates
extracted from the hippocampus [using peak from Milad et al. (13)]. (C) Parameter estimates extracted from second-level 1-sample t tests for each group and
condition using the extinguished vs. conditioned stimulus never paired with the shock (CS1E vs. CS–) contrasts. Error bars reflect standard errors. MBSR,
mindfulness-based stress reduction; MNI, Montreal Neurological Institute; SME, stress management education.

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 Biological
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Enhanced Retrieval of Extinguished Fear 50 Years

A Changes in funconal acvaon during recall of B Acvaon levels per group at each me-point
exnguished
g smuli [group x me]
supramarginal gyrus
2.5

1.5

Esmates at [56, -40, 24]

1

0.5 pre
0 post
-0.5

-1

-1.5

-2

-2.5 MBSR SME

peak [MNI coordinates] cluster size p FWEc

56, -40 24 60 < 0.05

C Funconal acvaon of the rSMG during exncon recall at post D Increases in hippocampal funconal connecvity to a
correlates with total pracce me for the MBSR group cluster in sensory cortex following MBSR
sensory cortex
20
Pracce me [hours]
Esmates at [56, -40, 24]

15

10

0
0 10 20 30 40 50
-5

-10
R=0.378, p=0.018
peak [MNI coordinates] cluster size p FWEc

52, -28, 56 139 < 0.05

Figure 3. (A) The results of group-by-time analysis mapped onto Conte69 atlas via Connectome Workbench using trilinear interpolation. (B) Parameter
estimates extracted from the peak [56, 240, 24], Brodmann area 40, using second-level 1-sample t tests for each group and condition using the extinguished
vs. conditioned stimulus never paired with the shock (CS1E vs. CS–) contrasts. Compared with the control intervention, the mindfulness-based stress
reduction (MBSR) intervention was associated with the higher engagement of a cluster in the right supramarginal gyrus (rSMG)/posterior parietal cortex. (C)
Neural activity (parameter estimates of blood oxygen level–dependent signal extracted from the peak following MBSR intervention) correlate with total amount
of home meditation practice during the MBSR intervention. (D) Changes in hippocampal functional connectivity during extinction recall following MBSR. FWEc,
cluster level familywise error; MNI, Montreal Neurological Institute; rSMG, right supramarginal gyrus.

between the left hippocampus and a cluster in the rSMG for and symmetrized percent change in hippocampal gray matter
the mindfulness group from pre to post (n = 42; MNI co- intensity following both interventions. No significant relation-
ordinates [44,230, 38]; k = 121; p = 0.002 uncorrected, false ships were found when examining alterations within the left
discovery rate p = .030). No significant relationships were hippocampus. Again, we repeated this analysis using the early
observed for the SME group or the between-groups analysis phase of recall. Change in pre– to post–mean hippocampal
(all FWE p values, p . .05). gray matter was associated with enhanced connectivity be-
tween the hippocampus and left dorsolateral prefrontal
Structural Changes in the Hippocampus Predict (Figure 4) (MNI coordinates [236, 54, 22]; k = 166; FWE p =
Enhanced Connectivity Between the Hippocampus .013) and retrosplenial (Figure 4) (MNI coordinates [22, 266,
and Contextual Cuing Regions During Early Phases 14]; k = 126; FWE p = .046) cortices following mindfulness
of Recall training.
We have previously demonstrated mindfulness-training related
increases in hippocampal gray matter density (41), which we DISCUSSION
speculated may be due in part to synaptogenesis (42). Adaptively responding to threat signals and updating the
Therefore, we examined the relationship between change in meaning of those signals as they change is critical for mental
hippocampal functional connectivity during extinction recall health. A failure to update stimulus-response associations has

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A Increases in funconal connecvity between the B Increases in funconal connecvity between the
hippocampus and dorsolateral prefrontal cortex hippocampus and retrosplenial cortex

peak [MNI coordinates] cluster size p FWEc peak [MNI coordinates] cluster size p FWEc

-36, 54, 22 166 < 0.05 22, -66, 14 126 < 0.05

dorsolateral prefrontal cortex retrosplenial cortex

Funconal connecvity with

Funconal connecvity with

1 1

0.5
hippocampus

hippocampus 0.5

0 0
-4 -2 0 2 4 -4 -2 0 2 4
-0.5 -0.5

-1 -1

-1.5 -1.5
Symmetrized percent change in hippocampal Symmetrized percent change in hippocampal
structure structure
Figure 4. Structural change in the hippocampus from pre to post predict increased functional connectivity between the hippocampus and dorsolateral prefrontal
(A) and retrosplenial (B) cortices during the early phases of recall at post for the mindfulness-based stress reduction group. The graphs show connectivity values
between the hippocampus and the dorsolateral prefrontal (A) and retrosplenial (B) cortices as they covary with symmetrized percent change in hippocampal signal
intensity. The x-axis depicts symmetrized percent change in hippocampal signal intensity, while the y-axis depicts the Fisher-transformed correlation coefficient of
connectivity between the hippocampus and the relevant cluster. FWEc, cluster level familywise error; MNI, Montreal Neurological Institute.

been implicated in the pathophysiology of several anxiety
disorders (43,44). Yet, ways to enhance the capacity to update
those associations and, more importantly, to retain and
retrieve these newly formed adaptive representations remain
largely unknown. Relying on the role of the hippocampus in
retrieval of contextual information to signal safety (5), we
postulated that mindfulness training would promote changes
in the hippocampus and thereby enhance extinction memory
retrieval. An investigation of functional activity during extinc-
tion recall demonstrated differential engagement of the
supramarginal gyrus following mindfulness training as well as
increased connectivity between the hippocampus and the
supramarginal gyrus during the early phase of extinction recall
for the mindfulness group. Providing further evidence for the
neuroadaptive changes associated with mindfulness training,
we found increased connectivity between the hippocampus
and primary somatosensory cortex, specifically in the area of
the primary somatosensory cortex that corresponds to where
the shock electrodes had been placed. These findings suggest
that strengthened hippocampal circuits following mindfulness
training are associated with enhanced retrieval of extinguished
fear memories and advocate extinction learning as a mecha-
nism through which mindfulness training may foster resilience
and reduce stress and anxiety.
Longitudinal changes in hippocampal structure and function
have long been thought to be key components in the devel-
opment of stress resilience following mindfulness training
(21,45). Changes in hippocampal structure and function have
also been reported following aerobic and strength training
(27,46). By comparing mindfulness training with an active
control that included exercise, we aimed to isolate the specific
effects of mindfulness training on hippocampal function. While
functional changes within the hippocampus were not specific
to mindfulness training, and the changes in functional activa-
tion and connectivity did not survive between group analyses,
only mindfulness training enhanced connectivity between the
hippocampus and a primary sensory cortex cluster where
participants had received the shock (i.e., the unconditioned
stimulus). This finding is in line with previously reported
increased sensory processing following mindfulness training

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Enhanced Retrieval of Extinguished Fear
(23) and may reflect mindfulness training’s strong emphasis on
heightened awareness of somatosensory information.
We previously demonstrated mindfulness training–
dependent influences on fear acquisition in a small pilot
study (47). Specifically, compared with a waitlist group, the
mindfulness training group exhibited no change in condi-
tioning from pre to post while the waitlist group exhibited
decreased conditioning. This differential conditioning was
correlated both with decreases in perceived stress and with
a significant increase in fractional anisotropy in the right
uncinate fasciculus. Although counterintuitive, this finding is
consistent with mindfulness instructions to bring attention
to present moment sensory experience with an accepting
and nonjudging attitude (48). The finding is also consistent
with previous studies with experienced meditation practi-
tioners that have demonstrated enhanced neural signal in
both primary and secondary sensory cortices during
experimentally induced pain (22,49), as well as decoupling
between sensory regions and frontal executive regions (50).
In line with these prior studies, we interpret our current
finding of enhanced hippocampal–primary somatosensory
cortex coupling during recall to indicate improved contex-
tual retrieval of sensory experience associated with extin-
guished stimuli. This finding implies that mindfulness
practice likely altered the conditioning as well as the
extinction processes. We will report the analysis of those
conditions elsewhere. All in all, the current results are
consistent with previous findings that one’s ability to pay
attention to sensory experience is a critical component of
extinction learning in therapeutic settings (50).
Mindfulness training programs emphasize the development
of focused attention and have been previously associated with
significant improvements in selective and executive attention
(51). In line with the pivotal role of attention in retrieval (52), we
observed enhanced activation in the rSMG. The rSMG has
been implicated in memory retrieval, specifically in directing
the attentional capture to task-relevant memory contents and
matching them with the current retrieval cue (53). This region
has been proposed to shift attention to, or maintain attention
on, internally generated mnemonic representations and direct
voluntary attention to memory contents, depending on task
demands (54,55). It is also part of the ventral frontoparietal
system that is thought to be involved in detecting unattended
or unexpected stimuli and triggering shifts of attention in a
bottom-up fashion (56). Accordingly, enhanced rSMG
engagement during retrieval, together with increased coupling
between the hippocampus during the early phase of retrieval,
may imply differential influence of mindfulness training on
attentional regulation to promote context-based extinction
recall. This interpretation is supported by the extensive
anatomical connectivity between the posterior parietal cortex
and the medial temporal lobe regions specifically involved in
retrieval (57), previous reports of SMG activation during the
retrieval of extinguished stimuli (13), and our observed corre-
lation between rSMG activation following mindfulness training
and reported practice time. The cross-hemisphere interaction
between the left hippocampus and rSMG is also in line with
left-lateralized retrieval–related medial temporal lobe activa-
tions (53,58) and right-lateralized perceptual attention–related
posterior parietal cortex activations (59). Together, these
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Biological
Psychiatry:
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findings highlight the significance of attentional processes
during extinction learning and suggest a mechanism through
which mindfulness training may differentially contribute to im-
provements in extinction recall.
In line with the plausible association between brain structure
and function, increases in hippocampal gray matter intensity
following mindfulness training predicted enhanced connectivity
between the hippocampus and the dorsolateral prefrontal cor-
tex (DLPFC) and retrosplenial cortex. Both regions have previ-
ously been shown to play a role in the recall of fear extinction
(60,61). DLPFC activation during extinction recall has specif-
ically been associated with reappraisal (62), the manipulation or
reinterpretation of the meaning of a conditioned stimulus (15),
and exposure therapy (50). Importantly, one the one hand,
increased connectivity within a DLPFC-cingulate-parietal-
hippocampal network has been associated with suppression
of previously encoded associations (63), which is important for
preventing memories of the conditioned stimulus from inter-
fering with the extinction memory. The retrosplenial cortex, on
the other hand, is structurally connected to parahippocampal
areas (57) and has also been implicated in episodic memory
(60,64). Critically, the degree of connectivity between the ret-
rosplenial cortex and other areas in the fear network has been
associated with the degree of contextual memory retrieval (65).
Improvements in the intrinsic connectivity of the retrosplenial
cortex have been previously reported following mindfulness
training as well (66). Given that the retrosplenial cortex can
bridge the medial temporal lobe and cortical default mode
network regions that underlie contextual processing during
episodic memory, we postulate that mindfulness-dependent
increases in hippocampal structure may underlie changes in
context-dependent neural activation patterns during retrieval
and may further contribute to cognitive and behavioral flexibility
through improved contextual processing within the default
mode network (67–69). Importantly, both the retrosplenial cortex
and DLPFC regions were identified only during the early phase
of recall, when contextual information would be most relevant
for cuing the memory representation.
It is important to note that although the study included an
active control group, the unequal allocation ratio could limit our
ability to detect effects in the control group owing to the low
power associated with the sample size. Future studies are
necessary to test whether the results persist with an equal
randomization ratio. Other limitations include the small sample
size for the skin conductance response analysis, owing to
technical difficulties associated with assessing the electro-
dermal signal. Although we were able to replicate previous
research findings (14) by demonstrating a positive association
between extinction retention and hippocampal activation at
baseline with a rather small sample, we lacked statistical po-
wer to detect improvements in extinction retention following
mindfulness training using skin conductance responses.
Future studies may utilize other metrics and/or criteria for
computing an index of extinction retention (70). Additionally,
the current sample included highly stressed but healthy in-
dividuals; future studies should investigate extinction recall
following mindfulness training in patient populations and using
personally relevant fear-inducing cues.
Impaired extinction recall has been implicated in the path-
ophysiology of several anxiety disorders (10,71,72). Successful
699
Biological
Psychiatry:
Celebrating
50 Years
retrieval of the extinction memory established during treatment
is critical to the efficacy of exposure-based therapy (73,74).
Previous investigations into the neural mechanisms associated
with exposure therapy revealed experience-dependent neural
adaptations in the hippocampus (75–77). Several other in-
terventions, including treatment with cortisol (78), selective
serotonin reuptake inhibitors (79), and psychotherapy (80),
have been associated with alterations in the hippocampus as
well. Accordingly, longitudinal changes in hippocampal struc-
ture and function have long been thought to be important for
the development of stress resilience following mindfulness
training (45). The current results, together with previously re-
ported morphological differences between meditators and
nonmeditators (18,19,41), suggest hippocampal-dependent
changes in contextual retrieval as one plausible mechanism
through which mindfulness-based interventions regulate af-
fective response, foster stress resilience, curtail susceptibility
to anxiety, and improve emotion regulation, while also advo-
cating a novel way to enhance fear extinction.
ACKNOWLEDGMENTS AND DISCLOSURES
This work was funded by National Institutes of Health Grant Nos. R01
AT006344 (to SWL), R21 AT003425 (to SWL), and R01 AG048351 (to SWL).
We thank Tom Callahan, Narayan Brach, Max Newlon, Patricia Pop, and
Yulia Kulminova for their assistance; the intervention providers Zayada
Vallejo and Jen Kelly; and our study participants.
The authors report no biomedical financial interests or potential conflicts
of interest.
ClinicalTrials.gov: Neural Correlates of Stress Reduction; https://
clinicaltrials.gov/ct2/show/NCT01488422; NCT01488422.
ARTICLE INFORMATION
From the Department of Psychiatry (GS, BKH, JG, TG, VB, MV, SPO, SWL),
Massachusetts General Hospital, Harvard Medical School, Boston, Mas-
sachusetts; Department of Neuroradiology (BKH), Klinikum rechts der Isar,
Technical University of Munich, Munich, Germany; Department of Anes-
thesia, Pain Management & Perioperative Medicine (JAH), Dalhousie Uni-
versity, Halifax, Nova Scotia, Canada; and the Psychiatry Department
(MRM), University of Illinois at Chicago, Chicago, Illinois.
MRM and SWL contributed equally to this work.
Address correspondence to Gunes Sevinc, Ph.D., Department of Psy-
chiatry, Division of Psychiatric Neuroscience, Massachusetts General
Hospital, Harvard Medical School, 120 2nd Avenue, Charlestown, MA
02129; E-mail: gsevinc@mgh.harvard.edu.
Received Dec 3, 2018; revised May 15, 2019; accepted May 16, 2019.
Supplementary material cited in this article is available online at https://
doi.org/10.1016/j.biopsych.2019.05.017.
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